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Bright Light Therapy in Parkinson's Disease: An Overview of the Background

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Hindawi Publishing Corporation
Parkinson’s Disease
Volume 2012, Article ID 767105, 9 pages
doi:10.1155/2012/767105

Review Article
Bright Light Therapy in Parkinson’s Disease:
An Overview of the Background and Evidence

Sonja Rutten,1, 2 Chris Vriend,1, 2 Odile A. van den Heuvel,1, 2 Jan H. Smit,1
Henk W. Berendse,3 and Ysbrand D. van der Werf2, 4
1 Department of Psychiatry, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
2 Department of Anatomy and Neuroscience, VU University Medical Center, Van der Boechorststraat 7,
1081 BT Amsterdam, The Netherlands
3 Department of Neurology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
4 Department of Sleep and Cognition, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences,

Meibergdreef 47, 1105 BA Amsterdam, The Netherlands

Correspondence should be addressed to Sonja Rutten, s.rutten@vumc.nl

Received 27 September 2012; Revised 16 November 2012; Accepted 21 November 2012

Academic Editor: Douglas Mckay Wallace

Copyright © 2012 Sonja Rutten et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Sleep disorders are common in Parkinson’s disease (PD) and seem to be strongly associated with depression. It has been
suggested that sleep disorders as well as depression are caused by a disturbed circadian rhythm. Indeed, PD patients are prone
to misalignment of their circadian rhythm due to various factors, and many patients with PD display a phase advance of their
circadian rhythm. Current treatment options for sleep disorders and depression in patients with PD are limited and can have
serious side effects; alternative treatments are therefore badly needed. Bright light therapy (BLT) restores circadian rhythmicity
effectively in mood- and sleep-disturbed patients without PD. The few studies that focused on the efficacy of BLT in patients
with PD demonstrated a positive effect of BLT not only on sleep and mood but also on motor function. More research on the
neurobiology and efficacy of BLT in PD is warranted.

1. Introduction at night, has been suggested to worsen motor symptoms in

In addition to the characteristic motor symptoms, patients
with Parkinson’s disease (PD) experience many nonmotor
symptoms, comprising a variety of cognitive, autonomic,
sensory, neuropsychiatric, and sleep disturbances [1, 2].
Sleep disturbances and disorders (as defined in Table 1)
including reduced total sleep time, reduced sleep efficiency,
increased sleep fragmentation, rapid eye movement (REM)
sleep behaviour disorder, and excessive daytime sleepiness,
occur in about 60–95% of PD patients [3–6]. Sleep influences
motor symptoms. The so-called “sleep benefit”, an improve-
ment of motor functions upon awakening that occurs in
more than 40% of PD patients, is attributed to improved
dopaminergic function as a result of increased storage
of dopamine in nigrostriatal terminals during sleep [7].
Moreover, melatonin, a hormone secreted by the pineal gland
PD patients [8].
Sleep disorders in PD often coincide with depression
[6]. Depression occurs in 35–50% of patients throughout
the course of the disease [9, 10]. It has a major impact on
overall functioning of PD patients: depressed PD patients
score lower on scales assessing activities of daily living and
exhibit more cognitive problems [9, 11, 12].
Sleep disorders and depression are two of the most
important factors influencing quality of life of PD patients
and their caregivers [4, 9, 13, 14]. Unfortunately, treatment
options are limited, and adding pharmacological agents
raises nonadherence in PD patients [15]. Moreover, medica-
tion can induce serious side effects in PD patients. Hypnotic
drugs, often prescribed for sleep disorders, worsen daytime
sedation and the risk of falling and are therefore less suitable
2 Parkinson’s Disease
Table 1: Definitions of sleep terminology.
Term
Sleep disturbance
Sleep disorder
Sleep onset latency
Sleep efficiency
Chronotype
Homeostatic sleep
drive
Sleep fragmentation
Sleep phase advance
Insomnia
REM sleep behavior
disorder
Excessive daytime
sleepiness
Periodic limb
movement disorder
Restless legs
syndrome
for PD patients [16]. Melatonin might ameliorate subjective
sleep disturbances in PD patients, but objective improvement
of sleep quality is minimal [17, 18]. Since a number of
studies indicate that melatonin has unfavorable motor effects
through interaction with dopamine pathways, more research
is warranted on the effects of exogenous melatonin in PD
patients [19–22].
Tricyclic antidepressants (TCAs), used in the treatment
of depression in PD, can cause orthostatic hypotension,
sedation, cognitive and anticholinergic adverse effects, in
addition to extrapyramidal adverse effects, that may poten-
tially worsen motor symptoms [23, 24]. Results of studies
focussing on the tolerability of selective serotonin reup-
take inhibitors (SSRIs) are inconclusive [23–25]. Levodopa
treatment can alleviate nocturnal akinesia and thus improve
sleep but can conversely negatively influence sleep by
reducing the duration of REM sleep and increasing REM
sleep latency [26]. Anticholinergics and dopamine agonists
increase the risk of nighttime hallucinations [27]. The
latter are also associated with sudden attacks of daytime
sleepiness [26], which may hamper quantity and qual-
ity of nighttime sleep. Behavioral and psychotherapeutic
Definition
Sleep pattern divergent of what is considered to be normal as
objectively measured, for example, by polysomnography.
Medical disorder involving sleep, resulting in suffering or reduced
functioning, including dyssomnias and parasomnias.
Time interval between time of turning of the lights and onset of sleep.
Ratio of the time spent asleep to the amount of time spent in bed.
Individual internal timing type regarding preferred time for mental
and physical activity and sleep.
Drive to sleep that gradually increases with prolonged wakefulness
and decreases during sleep.
Disrupted sleep cycle due to interruption of a sleep stage, as a result
of the appearance of a lighter sleep stage or wakefulness.
Forward shift of the sleep/wake rhythm, as demonstrated by the time
of the nocturnal elevation of plasma melatonin.
Sleep disorder comprising difficulty initiating and/or maintaining
sleep or nonrestorative sleep for at least one month, resulting in
significant distress and/or impaired daytime functioning
Parasomnia characterized by “acting out” of dreams during REM
sleep due to absence of normally occurring muscle atonia.
Parasomnia characterized by excessive sleepiness during the day,
often with hypersomnia and the occurrence of sleep attacks.
Sleep disorder characterized by involuntary limb movements causing
fragmented sleep.
Syndrome characterized by unpleasant sensations in one or more
limbs, exacerbated by rest and relieved with activity, paired with a
strong urge to move the affected limbs, often with paresthesias or
dysesthesias.
interventions are often less feasible due to cognitive dys-
function and dementia [28]. It is evident that there is
a great need for an effective and patient-friendly alter-
native for treating sleep disorders and depression in PD
patients.
Sleep problems and depressive symptoms often cooccur
in PD [6, 14]. Dysfunction of the biological clock might
be a common underlying causal factor for these disorders,
providing a promising potential target for treatment [29, 30].
Bright light therapy (BLT) restores circadian rhythmicity and
therefore effectively treats affective disorders and insomnia,
and increases sleep efficiency [31–38]. Additionally, it might
lead to improvement of motor symptoms in PD [8, 39, 40].
BLT has few contraindications and side effects and may
therefore be an elegant alternative for the treatment of PD-
related depression and sleep disturbances.
This paper gives an overview of the neurobiology of
the biological clock and the factors that contribute to its
desynchronization in PD. Furthermore, we review the evi-
dence for BLT as a treatment for sleep disorders, depression
and motor symptoms in patients with PD, and provide
recommendations for administration of BLT.
Parkinson’s Disease
2. The Circadian Rhythm and Consequences of
Desynchronization
To understand the effects of BLT, one needs to understand
the (patho)physiology of circadian rhythmicity, as explained
in this section. The circadian rhythm is generated by the cir-
cadian pacemaker, a group of about 10,000 neurons located
in the suprachiasmatic nucleus (SCN) of the hypothalamus.
Its endogenous rhythm is slightly different from the 24-
hour day-night cycle and has to be entrained by signals (or
“zeitgebers”) such as light, activity, and food [41]. Light
excites specialized melanopsin containing ganglion cells in
the retina, that project a “daytime” signal towards the SCN
via the retinohypothalamic tract [42]. The output signals of
the SCN convey circadian timing information to brain areas
regulating behavior, body temperature, autonomic and neu-
roendocrine systems, including the secretion of melatonin by
the pineal gland [42]. The secretion of melatonin is inhibited
by the SCN during the light cycle, but the SCN also contains
melatonin receptors that inhibit SCN firing, thereby creating
a negative feedback loop [43, 44].
Desynchronization of the biological clock can be caused
by a variety of factors that influence the input of the SCN
[45]. A disturbed circadian rhythm is probably a major com-
mon causal factor in both depression and sleep problems [29,
46, 47]. Some of the major neurotransmitters implicated in
mood regulation, including serotonin, norepinephrine, and
dopamine, as well as their receptors, show a circadian rhythm
in their levels, release, and activity [48]. Various polymorphic
variations of clock genes such as TIM, BMAL1, and PER2
are associated with mood disorders [29]. Research on the
diurnal variability of mood has shown that misalignment of
the circadian rhythm can induce mood changes [47]. Some
patients with a depressive disorder display a phase advance
in circadian rhythm, as exhibited by a shift in melatonin and
cortisol rhythms [36, 47]. Dysfunction of the circadian clock
can lead to sleep fragmentation or insomnia [42, 45].
The interaction between sleep and depression likely
comprises more than a failure of the biological clock.
Insomnia or hypersomnia are well-known symptoms of
depression, but sleep disturbances can cause depressive
symptoms as well [29, 47, 49–55]. Emotional hyperarousal
may increase autonomic activity, resulting in sleep difficulties
[53]. This is confirmed by the fact that depressed patients
show altered sleep architecture, which normalizes after
successful treatment [50]. On the other hand, emotionality
is frequently negatively toned in insomnia and poor sleep
[47, 51], and studies on sleep deprivation showed enhanced
emotional physiological responses to negative stimuli [49,
52, 55]. During REM sleep, emotional intensity of previous
affective experiences is decreased [54, 56, 57]. Functional
Magnetic Resonance Imaging (fMRI) studies show that sleep
deprivation leads to increased activation of the amygdala in
response to negative aversive stimuli [58–60]. These findings
strongly suggest that sleep is relevant for maintaining
adaptive emotional regulation and reactivity [29, 54].
In short, sleep disturbances and depression seem to be
highly correlated. A disturbed biological rhythm might be
a common underlying factor and therefore an important
3
starting point for treatment. However, the directionality of
the relationship between these three remains uncertain, and
more research on this subject is warranted.
3. Desynchronization of the Circadian Rhythm
in Parkinson’s Disease
PD patients are prone to desynchronization of their biolog-
ical clock due to various factors that will be discussed in
this section. The neurodegenerative process in PD leading
to dopamine depletion is one of the underlying causes,
since recent research links dopamine directly to the circadian
rhythm [61–63]. Striatal dopamine metabolism seems to be
regulated by clock proteins such as PER2 [62]. Reciprocally,
stimulation of dopamine receptors affects the rhythm of
expression of clock genes such as PER1 and PER2 in the
striatum [61, 63]. Dopamine also regulates the rhythmic
expression of melanopsin in retinal ganglion cells, thereby
influencing the entrainment of the circadian rhythm by light
[64].
In many patients with PD, factors hampering the
SCN input contribute to desynchronization of the circa-
dian rhythm. Firstly, exposure and sensitivity to zeitgebers
decrease. Retinal illumination decreases in the elderly due
to pupillary miosis and reduced crystalline lens light trans-
mission, especially of short wavelengths [65]. This leads
to partial light deprivation of the SCN and pineal gland.
Additionally, PD patients, just like many elderly patients,
may be more inclined to stay indoors due to motor problems
or a decreased postural balance and expose themselves less to
environmental light and physical activities [45]. Entrainment
of the circadian rhythm is thwarted by a decreased exposure
to zeitgebers.
The amplitude of the circadian rhythm decreases in
patients with PD, as reflected by a decrease in sympathetic
activity during the day, diminishing of the diurnal variation
of cortisol secretion, and a decrease of the amplitude of the
melatonin secretion rhythm [19, 66, 67]. This flattening of
circadian rhythms makes them more prone to desynchro-
nization.
Sleep in PD patients can be disrupted by both motor
(e.g., nocturnal akinesia and dystonia) and nonmotor symp-
toms such as nocturia [1, 68]. Additionally, PD patients
may experience periodic limb movement disorder, restless
legs syndrome, REM sleep behavior disorder, and excessive
daytime sleepiness [4, 26, 68], all contributing to a reduced
quality and/or quantity of sleep. PD-related neuropsychiatric
disorders such as benign hallucinations and psychosis can
also disturb sleep [6]. Emotional stress, caused by having
a progressive neurodegenerative disorder that increasingly
results in disability, may interact with the basic homeostatic
and circadian drives for sleep through the interaction
between affect-related regions and regions that control sleep
and wake [30]. A disturbed sleep-wake cycle results in
conflicting SCN input.
Finally, pharmacological treatment of PD with dopamin-
ergic drugs also influences sleep/wakefulness mechanisms.
Levodopa use can lead to a decrease of sympathetic activity
4 Parkinson’s Disease
during the day and disappearance of the sympathetic
morning peak [69]. Levodopa influences sleep architecture,
reducing the duration of REM sleep and increasing REM
sleep latency [26].
All of the abovementioned factors may contribute to
a desynchronization of the circadian rhythm in PD, as
displayed in Figure 1. In several small studies, levodopa-
treated PD patients display a phase-advanced circadian
rhythm compared to healthy controls and de novo PD
patients [19, 70, 71], making them vulnerable to depression
and sleep disorders. Indeed, PD patients have more frequent
awakenings at night and a reduced sleep efficiency compared
to healthy controls [68]. BLT acts as a strong zeitgeber and
may therefore restore circadian rhythmicity in PD patients.
4. Efficacy of Bright Light Therapy
In the last couple of years, research on the efficacy of BLT
has shifted from adults to the elderly and specifically to PD
patients. In 2005 a meta-analysis demonstrated that BLT is
effective in treating seasonal affective disorder (SAD) and
nonseasonal depression in adults, with effect sizes equivalent
or superior to psychopharmacologic treatment [31]. BLT has
few side effects and is therefore considered a patient-friendly
treatment [32, 72].
Two recent large randomized controlled trials focused on
the efficacy of BLT for nonseasonal depression in the elderly
[32, 33]. Lieverse et al. stated that the positive effects of BLT
were due to improved circadian rhythmicity, as displayed in
their study by (1) an increased steepness of the evening rise of
salivary melatonin levels, (2) a reduction of 24-hour urinary
cortisol excretion, and (3) a trend-significant accelerated
diurnal decline in salivary cortisol levels [32]. Riemersma-
van der Lek et al. demonstrated that BLT attenuated cognitive
and functional decline and positively influenced mood in 189
residents of group care facilities, of which 87% had dementia.
In this study, BLT only improved sleep when it was combined
with the administration of melatonin [33]. In other studies,
BLT as monotherapy was effective in improving both sleep
efficiency and quality and in reducing daytime sleepiness in
elderly patients with and without dementia [32, 34, 35, 37].
To summarize, BLT seems to be effective in treating sleep
disorders as well as depression. Most of the abovementioned
studies, however, excluded patients with disorders such as
PD. Only four studies have addressed the use of BLT in
PD [8, 39, 40, 73]; these will be discussed in the following
section. The first study in which BLT was used in PD patients
is only available in Russian and is therefore not included in
this overview [73].
Willis and Turner described a case series of 12 patients
with PD and insomnia and/or depressive symptoms [40].
They used BLT of 1000–1500 Lux for 60 to 90 minutes prior
to normal bedtime during two to five weeks. Of the eight
participants that reported significant problems with falling
asleep, seven showed improvement in the onset and conti-
nuity of sleep after BLT treatment. Most patients reported
this effect within two to three days after commencing BLT,
and this lasted for several days after discontinuation. Six
of 11 patients showed a noticeable improvement of mood.
The antidepressant effect lasted for several weeks, even after
discontinuation of BLT, and was paralleled by increased
socialization. BLT resulted in improved motor function in
most PD patients, with the strongest effects on bradykinesia
and rigidity. After BLT, dopamine replacement therapy was
reduced to a level ranging from 13 to 100% in five subjects,
while antidepressants and hypnotic drugs were reduced or
eliminated in two patients. Younger patients, especially those
that were medication naı̈ve, responded better to BLT than
those over 75 years of age, and adherent patients had a better
therapeutic response than those who used it intermittently.
In a RCT by Paus et al., 18 PD patients treated with
BLT of 7500 Lux were compared to 18 PD patients receiving
placebo light of 950 Lux [39]. Light was administered
for 30 minutes in the morning during two weeks. PD-
related symptoms were assessed with the Unified Parkinson’s
Disease Rating Scale (UPDRS); depression was measured
with the Beck Depression Inventory (BDI). Patients who
received BLT showed a significant improvement on UPDRS
sections I (evaluation of mentation, behavior, and mood),
II (self-evaluation of the activities of daily life), and IV
(Hoehn and Yahr Scale) compared with the control group.
Improvement of UPDRS I and II did not correlate with
changes in BDI scores, implying that the effects of BLT on
behavior and daily functioning were independent of changes
in mood. There was no significant difference on UPDRS
section III (clinician-scored motor evaluation), except for a
slight attenuation of tremor. Regarding sleep, the only sleep
parameter investigated was a one-item daytime sleepiness
scale, which did not show a between-group difference. Mood
improved significantly, but moderately, in the BLT group, as
demonstrated by an average decrease of 2.2 points on the
BDI. No significant improvement of BDI scores occurred
in the control group. The short treatment duration and the
fact that only mildly depressed patients were included might
explain the modest effects of BLT on motor function and
depression [49].
(Willis et al. 2012, [8]) performed a retrospective, open
label study monitoring 129 levodopa-treated PD patients
for a period ranging from a few months to eight years
[49]. These patients were all prescribed BLT at a dose of
4000 to 6000 Lux for one hour prior to bedtime. Depending
on the degree of adherence, PD patients were divided in
the early quit group (EQUIT; patients that withdrew from
BLT immediately after intake), the adherent group and the
semiadherent group. Twelve patients suffering from other
neurological conditions served as a control group. Motor
function was assessed with three timed motor tests and a
global rating scale. Psychiatric symptoms and sleep were
evaluated on a global rating scale during an interview. Total
drug burden (TDB) was determined and monitored over
time. There was a slight deterioration of insomnia seen in
EQUIT patients, while adherent patients showed an acute
and dramatic improvement. Adherent patients displayed a
significant improvement of bradykinesia, rigidity, balance,
and motor tests, while the motor parameters in the EQUIT
group deteriorated over time. In the semiadherent group,
these parameters varied over time and appeared associated
Parkinson’s Disease 5

- Decreased retinal illumination Dysregulation circadian

Treatment with levodopa
- Decreased mobility/exercise clock gene expression

Input Biological clock Output

propensity
Sleep
sympathetic activity
Melatonin, cortisol,
Time

- Sleep disrupting motor symptoms

- Sleep disrupting autonomic symptoms
- Sleep disrupting neuropsychiatric
symptoms
- PD-related sleep disorders

Figure 1: The input of the biological clock by zeitgebers is both decreased and conflicted due to various motor and non-motor symptoms in
PD. Dopamine depletion due to PD disrupts circadian clock gene expression, and its treatment with levodopa influences both sleep structure
and sympathetic activity. These factors all alter output of the biological clock: there is a phase advance and flattening of the circadian rhythm
as displayed by hormone levels and sympathetic activity. In turn, the alteration of circadian rhythmicity has a negative influence on (input
of) the biological clock, leading to a downward spiral resulting in sleep disturbances and depression.

with periods of nonadherence with BLT or changes in drug
regimen. All groups displayed an improvement of depression
over time, with the most robust improvement seen in adher-
ent patients. Anxiety did not change in the EQUIT group in
contrast to other groups, with the greatest improvement in
the adherent group. The adherent and semiadherent groups
required an increase in TDB in, respectively, 13 and 15%
of cases, while 91% in the EQUIT group required increased
medication. Moreover, patients in the EQUIT group were
on similar doses of dopamine replacement therapy as the
other PD patients but displayed more severe PD than
those who received BLT. In the adherent group, morbidity
improved over the course of years, while in the EQUIT group,
progression of PD severity was as expected. Limitations of
this study are the fact that the study was not blinded or
placebo controlled, and that patients were monitored for
different periods of time.
Depression can lead to psychomotor retardation [74], so
the improvement of motor function in these studies could be
attributed to a decrease in depressive symptoms. However, in
the study by Paus et al (2007). there was no improvement
of motor function in the subjects that demonstrated a
significant decrease of the BDI score [39]. More likely, the
positive effects of BLT on motor symptoms in PD result from
a restored balance between melatonin and dopamine [8]. A
number of studies indicate that melatonin has unfavorable
motor effects through interaction with dopamine pathways
[19–22].
Another point that is not addressed in these studies
is the effect of other zeitgebers on the improvement in
circadian rhythmicity. All subjects were given BLT at a set
time, prior to bedtime or after awakening in the morning.
This may have improved the daily rhythm and sleep-wake
cycle of participating patients. Behavioral and psychological
interventions are also effective in treating insomnia [75, 76].
Taken together, these studies display a positive effect of
BLT on mood, sleep, and motor functions in PD patients.
However, since these studies were relatively small and
suboptimally designed, further studies on the efficacy of BLT
in treating both nonmotor motor and motor symptoms in
patients with PD are warranted.
5. Recommendations for Administration of BLT
In this section, recommendations for administration of BLT
as well as information on contraindications and adverse
effects are provided. Due to a lack of research on BLT in PD
6 Parkinson’s Disease
patients, the majority of these recommendations are based
on research in patients without PD, so we must stress that
(adverse) effects in PD patients might be different. More
research on the effects of BLT in PD patients needs to be
done before BLT can be used for PD patients in daily clinical
practice.
There are many types of light boxes available. Clinically
tested models yield a maximum illuminance of 10.000 Lux
at a comfortable sitting distance of about 30 cm [38, 77]. At
this intensity, a duration of 30 minutes per session is usually
sufficient, while lower intensities require longer sessions [31,
78, 79]. It is advisable to use a light box with a complete
ultraviolet (UV) filter, since cumulative UV radiation can be
harmful to eyes and skin [80, 81].
Time of administration of BLT depends on the nature
of the patient’s complaints and his or her individual
chronotype. Morning light advances the biological clock
and has proven to be effective in treatment of depression
[77, 78]. However, patients with PD probably have a phase-
advanced circadian rhythm, and one might argue that
evening BLT might be more efficient [8, 19, 40, 70, 71].
On the other hand, Paus et al. (2007) demonstrated that
morning light can improve mood and sleep in PD patients
as well [39]. BLT is most effective when administered relative
to individual chronotype [38, 82]. The chronotype can be
assessed with the Morningness-Eveningness Questionnaire
(MEQ), which correlates with the time of onset of evening
rise in melatonin secretion and circadian variation of oral
temperature [78, 82, 83]. An online version of the MEQ at
the website of the Center for Environmental Therapeutics
(http://www.cet.org/) contains a table of the recommended
timing of morning BLT based on the MEQ-score. Strict
adherence to BLT is necessary to maximize efficacy [8].
There is no consensus on the total duration of treatment
with BLT in nonseasonal depression or insomnia. In PD
patients, followup after discontinuation of BLT was only
performed in the study of Willis and Turner (2007) [40].
They observed that the antidepressant effect of BLT lasted
after discontinuation of therapy, but sleep deteriorated after
a couple of days. These findings correspond with a large
study on the effects of BLT in the elderly patients with a
nonseasonal depression [32]. Since it might take months
before BLT can exert positive effects on motor function, a
long treatment duration of PD patients might be necessary
[8]. More research on both timing and duration of BLT in
patients with PD is warranted.
Cumulative light energy can cause damage to skin and
eye tissues, especially short-wavelength UV light [78, 80,
81]. Patients with porfyria, macular degeneration, retinal
dystrophy, lupus erythematosus, chronic actinic dermatitis,
and solar urticaria can have photosensitization reactions
to light and should only receive BLT under monitoring of
an ophthalmologist or dermatologist [78]. Moreover, some
pharmacological agents are known to photosensitize the skin
or retina, including some of the tricyclic antidepressants,
tetracyclic antibiotics, and antiarrhythmic drugs [78]. These
medications should be stopped before commencing BLT.
In a study of 70 subjects receiving BLT for a SAD the
most often reported adverse effects were headache, eye or
vision problems and nausea [72]. No oculoretinal changes
were detected during ophthalmologic evaluations of patients
receiving treatment with BLT to up to six years [84]. Some
cases of BLT-induced (hypo)mania have been described,
requiring discontinuation of BLT and medication [72, 85,
86]. However, in patients with a known or suspected bipolar
disorder BLT can be administered when the patient is using
a mood stabilizer [80]. Nevertheless, side effects of BLT are
mostly mild and usually resolve within a couple of days
[32, 33, 72].
6. Conclusion
Sleep disturbances are common in PD and are strongly
associated with depression [3–6]. A disturbed circadian
rhythm may be a common underlying factor in both
disorders [29, 46, 47]. PD patients are prone to misalignment
of the circadian rhythm due to dopamine deficiency as well as
various other factors that disrupt input to the SCN [1, 4, 26,
45, 63, 66, 68]. Indeed, many patients with PD display a phase
advance of their circadian rhythm [19, 70, 71], which may
contribute to the increased prevalence of sleep disturbances
and depression [6, 9, 10].
Since the current treatment options for sleep distur-
bances and depression in PD are limited and can have
serious side effects [16, 23], alternative treatments are badly
needed. BLT restores circadian rhythmicity and is an effective
treatment for depressive disorders and insomnia in the
general population [31–35, 37]. So far, little research has
focused on the efficacy of BLT in patients with PD [8,
39, 40, 73]. The studies that have been performed were
small and suboptimally designed yet demonstrated a positive
effect of BLT on sleep and mood in patients with PD.
Moreover, BLT may positively influence motor function,
possibly through a restored balance between melatonin and
dopamine [8, 40]. It might thus facilitate a dose reduction
of dopaminergic medication [8, 40]. BLT has few side-
effects and is therefore patient friendly [32, 72]. Nevertheless,
more research is warranted to demonstrate the efficacy and
underlying mechanism of BLT in PD.
References
[1] A. Park and M. Stacy, “Non-motor symptoms in Parkinson’s
disease,” Journal of Neurology, vol. 256, no. 3, supplement, pp.
293–298, 2009.
[2] M. C. Rodriguez-Oroz, M. Jahanshahi, P. Krack et al., “Initial
clinical manifestations of Parkinson’s disease: features and
pathophysiological mechanisms,” The Lancet Neurology, vol. 8,
no. 12, pp. 1128–1139, 2009.
[3] K. R. Chaudhuri, D. G. Healy, and A. H. V. Schapira,
“Non-motor symptoms of Parkinson’s disease: diagnosis and
management,” The Lancet Neurology, vol. 5, no. 3, pp. 235–
245, 2006.
[4] Y. Dauvilliers, “Insomnia in patients with neurodegenerative
conditions,” Sleep Medicine, vol. 8, supplement 4, pp. S27–S34,
2007.
[5] M. Menza, R. D. Dobkin, H. Marin, and K. Bienfait, “Sleep
disturbances in Parkinson’s disease,” Movement Disorders, vol.
25, supplement 1, pp. S117–S122, 2010.
Parkinson’s Disease
[6] J. P. Larsen and E. Tandberg, “Sleep disorders in patients with
Parkinson’s disease: epidemiology and management,” CNS
Drugs, vol. 15, no. 4, pp. 267–275, 2001.
[7] E. Tandberg, J. P. Larsen, and K. Karlsen, “Excessive day-
time sleepiness and sleep benefit in Parkinson’s disease: a
community-based study,” Movement Disorders, vol. 14, no. 6,
pp. 922–927, 1999.
[8] G. L. Willis, C. Moore, and S. M. Armstrong, “A historical
justification for and retrospective analysis of the systematic
application of light therapy in Parkinson’s disease,” Reviews in
the Neurosciences, vol. 23, no. 2, pp. 199–226, 2012.
[9] D. Aarsland, S. Pahlhagen, C. G. Ballard, U. Ehrt, and P. Sven-
ningsson, “Depression in Parkinson disease—epidemiology,
mechanisms and management,” Nature Reviews Neurology,
vol. 8, no. 1, pp. 35–47, 2012.
[10] J. L. Cummings, “Depression and Parkinson’s disease: a
review,” American Journal of Psychiatry, vol. 149, no. 4, pp.
443–454, 1992.
[11] A. Schrag, M. Jahanshahi, and N. Quinn, “What contributes to
quality of life in patients with Parkinson’s disease?” Journal of
Neurology, Neurosurgery & Psychiatry, vol. 69, no. 3, pp. 308–
312, 2000.
[12] K. H. Karlsen, J. P. Larsen, E. Tandberg, and J. G. Maeland,
“Influence of clinical and demographic variables on quality of
life in patients with Parkinson’s disease,” Journal of Neurology,
Neurosurgery & Psychiatry, vol. 66, no. 4, pp. 431–435, 1999.
[13] J. J. M. Askenasy, “Sleep in Parkinson’s disease,” Acta Neuro-
logica Scandinavica, vol. 87, no. 3, pp. 167–170, 1993.
[14] M. Caap-Ahlgren and O. Dehlin, “Insomnia and depressive
symptoms in patients with Parkinson’s disease: relationship
to health-related quality of life. An interview study of patients
living at home,” Archives of Gerontology and Geriatrics, vol. 32,
no. 1, pp. 23–33, 2001.
[15] M. B. Aerts, M. van der Eijk, K. Kramers, and B. R. Bloem,
“Insufficient medication compliance in Parkinson’s disease,”
Nederlands Tijdschrift voor Geneeskunde, vol. 155, p. A3031,
2011.
[16] M. J. Thorpy, “Sleep disorders in Parkinson’s disease,” Clinical
Cornerstone, vol. 6, no. 1, pp. S7–S15, 2004.
[17] G. A. Dowling, J. Mastick, E. Colling, J. H. Carter, C. M.
Singer, and M. J. Aminoff, “Melatonin for sleep disturbances
in Parkinson’s disease,” Sleep Medicine, vol. 6, no. 5, pp. 459–
466, 2005.
[18] C. A. M. Medeiros, P. F. Carvalhedo de Bruin, L. A. Lopes,
M. C. Magalhães, M. de Lourdes Seabra, and V. M. Sales de
Bruin, “Effect of exogenous melatonin on sleep and motor
dysfunction in Parkinson’s disease: a randomized, double
blind, placebo-controlled study,” Journal of Neurology, vol.
254, no. 4, pp. 459–464, 2007.
[19] R. Bordet, D. Devos, S. Brique et al., “Study of circadian
melatonin secretion pattern at different stages of Parkinson’s
disease,” Clinical Neuropharmacology, vol. 26, no. 2, pp. 65–72,
2003.
[20] H. Chen, E. Schernhammer, M. A. Schwarzschild, and A.
Ascherio, “A prospective study of night shift work, sleep
duration, and risk of Parkinson’s disease,” American Journal of
Epidemiology, vol. 163, no. 8, pp. 726–730, 2006.
[21] M. D. Catalá, C. Cañete-Nicolás, A. Iradi, F. J. Tarazona,
J. M. Tormos, and A. Pascual-Leone, “Melatonin levels in
Parkinson’s disease: drug therapy versus electrical stimulation
of the internal globus pallidus,” Experimental Gerontology, vol.
32, no. 4-5, pp. 553–558, 1997.
[22] G. L. Willis and S. M. Armstrong, “A therapeutic role for
melatonin antagonism in experimental models of Parkinson’s
7
disease,” Physiology and Behavior, vol. 66, no. 5, pp. 785–795,
1999.
[23] F. J. E. Vajda and C. Solinas, “Current approaches to manage-
ment of depression in Parkinson’s disease,” Journal of Clinical
Neuroscience, vol. 12, no. 7, pp. 739–743, 2005.
[24] S. Madhusoodanan, L. Alexeenko, R. Sanders, and R. Brenner,
“Extrapyramidal symptoms associated with antidepressants—
a review of the literature and an analysis of spontaneous
reports,” Annals of Clinical Psychiatry, vol. 22, no. 3, pp. 148–
156, 2010.
[25] I. H. Richard, M. P. McDermott, R. Kurlan, J. M. Lyness,
P. G. Como, N. Pearson et al., “A randomized, double-
blind, placebo-controlled trial of antidepressants in Parkinson
disease,” Neurology, vol. 78, no. 16, pp. 1229–1236, 2012.
[26] C. L. Deschenes and S. M. McCurry, “Current treatments
for sleep disturbances in individuals with dementia,” Current
Psychiatry Reports, vol. 11, no. 1, pp. 20–26, 2009.
[27] R. Pahwa, “Understanding Parkinson’s disease: an update on
current diagnostic and treatment strategies,” Journal of the
American Medical Directors Association, vol. 7, supplement 2,
no. 7, pp. 4–10, 2006.
[28] D. Aarsland, J. Zaccai, and C. Brayne, “A systematic review
of prevalence studies of dementia in Parkinson’s disease,”
Movement Disorders, vol. 20, no. 10, pp. 1255–1263, 2005.
[29] P. Monteleone and M. Maj, “The circadian basis of mood
disorders: recent developments and treatment implications,”
European Neuropsychopharmacology, vol. 18, no. 10, pp. 701–
711, 2008.
[30] C. Baglioni, K. Spiegelhalder, C. Lombardo, and D. Riemann,
“Sleep and emotions: a focus on insomnia,” Sleep Medicine
Reviews, vol. 14, no. 4, pp. 227–238, 2010.
[31] R. N. Golden, B. N. Gaynes, R. D. Ekstrom et al., “The
efficacy of light therapy in the treatment of mood disorders:
a review and meta-analysis of the evidence,” American Journal
of Psychiatry, vol. 162, no. 4, pp. 656–662, 2005.
[32] R. Lieverse, E. J. W. van Someren, M. M. A. Nielen, B. M.
J. Uitdehaag, J. H. Smit, and W. J. G. Hoogendijk, “Bright
light treatment in elderly patients with nonseasonal major
depressive disorder: a randomized placebo-controlled trial,”
Archives of General Psychiatry, vol. 68, no. 1, pp. 61–70, 2011.
[33] R. F. Riemersma-van der Lek, D. F. Swaab, J. Twisk, E. M.
Hol, W. J. G. Hoogendijk, and E. J. W. van Someren, “Effect
of bright light and melatonin on cognitive and noncognitive
function in elderly residents of group care facilities: a ran-
domized controlled trial,” The Journal of the American Medical
Association, vol. 299, no. 22, pp. 2642–2655, 2008.
[34] S. S. Campbell, D. Dawson, and M. W. Anderson, “Alleviation
of sleep maintenance insomnia with timed exposure to bright
light,” Journal of the American Geriatrics Society, vol. 41, no. 8,
pp. 829–836, 1993.
[35] K. Mishima, M. Okawa, Y. Hishikawa, S. Hozumi, H. Hori,
and K. Takahashi, “Morning bright light therapy for sleep and
behavior disorders in elderly patients with dementia,” Acta
Psychiatrica Scandinavica, vol. 89, no. 1, pp. 1–7, 1994.
[36] G. Pail, W. Huf, E. Pjrek et al., “Bright-light therapy in the
treatment of mood disorders,” Neuropsychobiology, vol. 64, no.
3, pp. 152–162, 2011.
[37] A. Satlin, L. Volicer, V. Ross, L. Herz, and S. Campbell,
“Bright light treatment of behavioral and sleep disturbances
in patients with Alzheimer’s disease,” American Journal of
Psychiatry, vol. 149, no. 8, pp. 1028–1032, 1992.
[38] A. Wirz-Justice, F. Benedetti, M. Berger et al., “Chronother-
apeutics (light and wake therapy) in affective disorders,”
Psychological Medicine, vol. 35, no. 7, pp. 939–944, 2005.
8 Parkinson’s Disease
[39] S. Paus, T. Schmitz-Hübsch, U. Wüllner, A. Vogel, T. Klock-
gether, and M. Abele, “Bright light therapy in Parkinson’s
disease: a pilot study,” Movement Disorders, vol. 22, no. 10, pp.
1495–1498, 2007.
[40] G. L. Willis and E. J. D. Turner, “Primary and secondary fea-
tures of Parkinson’s disease improve with strategic exposure to
bright light: a case series study,” Chronobiology International,
vol. 24, no. 3, pp. 521–537, 2007.
[41] D. K. Welsh, D. E. Logothetis, M. Meister, and S. M.
Reppert, “Individual neurons dissociated from rat suprachi-
asmatic nucleus express independently phased circadian firing
rhythms,” Neuron, vol. 14, no. 4, pp. 697–706, 1995.
[42] A. M. Rosenwasser, “Functional neuroanatomy of sleep and
circadian rhythms,” Brain Research Reviews, vol. 61, no. 2, pp.
281–306, 2009.
[43] J. Arendt and D. J. Skene, “Melatonin as a chronobiotic,” Sleep
Medicine Reviews, vol. 9, no. 1, pp. 25–39, 2005.
[44] S. R. Pandi-Perumal, I. Trakht, V. Srinivasan et al., “Physiolog-
ical effects of melatonin: role of melatonin receptors and signal
transduction pathways,” Progress in Neurobiology, vol. 85, no.
3, pp. 335–353, 2008.
[45] E. J. W. van Someren, “Circadian and sleep disturbances in the
elderly,” Experimental Gerontology, vol. 35, no. 9-10, pp. 1229–
1237, 2000.
[46] C. Cajochen, M. Münch, V. Knoblauch, K. Blatter, and
A. Wirz-Justice, “Age-related changes in the circadian and
homeostatic regulation of human sleep,” Chronobiology Inter-
national, vol. 23, no. 1-2, pp. 461–474, 2006.
[47] A. Wirz-Justice, “Diurnal variations of depressive symptoms,”
Dialogues in Clinical Neuroscience, vol. 10, no. 3, pp. 337–343,
2008.
[48] C. A. McClung, “Circadian genes, rhythms and the biology of
mood disorders,” Pharmacology and Therapeutics, vol. 114, no.
2, pp. 222–232, 2007.
[49] P. L. Franzen, D. J. Buysse, R. E. Dahl, W. Thompson, and
G. J. Siegle, “Sleep deprivation alters pupillary reactivity
to emotional stimuli in healthy young adults,” Biological
Psychology, vol. 80, no. 3, pp. 300–305, 2009.
[50] D. J. Buysse, E. Frank, K. K. Lowe, C. R. Cherry, and D. J.
Kupfer, “Electroencephalographic sleep correlates of episode
and vulnerability to recurrence in depression,” Biological
Psychiatry, vol. 41, no. 4, pp. 406–418, 1997.
[51] C. A. Espie, “Insomnia: conceptual issues in the development,
persistence, and treatment of sleep disorder in adults,” Annual
Review of Psychology, vol. 53, pp. 215–243, 2002.
[52] P. L. Franzen, G. J. Siegle, and D. J. Buysse, “Relationships
between affect, vigilance, and sleepiness following sleep depri-
vation,” Journal of Sleep Research, vol. 17, no. 1, pp. 34–41,
2008.
[53] A. Kales, A. B. Caldwell, T. A. Preston et al., “Personality
patterns in insomnia. Theoretical implications,” Archives of
General Psychiatry, vol. 33, no. 9, pp. 1128–1134, 1976.
[54] M. P. Walker and E. van der Helm, “Overnight therapy? The
role of sleep in emotional brain processing,” Psychological
Bulletin, vol. 135, no. 5, pp. 731–748, 2009.
[55] D. Zohar, O. Tzischinsky, R. Epstein, and P. Lavie, “The effects
of sleep loss on medical residents’ emotional reactions to work
events: a cognitive-energy model,” Sleep, vol. 28, no. 1, pp. 47–
54, 2005.
[56] K. J. Maloney, E. G. Cape, J. Gotman, and B. E. Jones, “High-
frequency γ electroencephalogram activity in association with
sleep-wake states and spontaneous behaviors in the rat,”
Neuroscience, vol. 76, no. 2, pp. 541–555, 1997.
[57] E. G. Cape and B. E. Jones, “Differential modulation of high-
frequency γ-electroencephalogram activity and sleep-wake
state by noradrenaline and serotonin microinjections into the
region of cholinergic basalis neurons,” Journal of Neuroscience,
vol. 18, no. 7, pp. 2653–2666, 1998.
[58] S. S. Yoo, N. Gujar, P. Hu, F. A. Jolesz, and M. P. Walker, “The
human emotional brain without sleep—a prefrontal amygdala
disconnect,” Current Biology, vol. 17, no. 20, pp. R877–R878,
2007.
[59] E. van der Helm, J. Yao, S. Dutt, V. Rao, J. M. Saletin, and
M. P. Walker, “REM sleep depotentiates amygdala activity to
previous emotional experiences,” Current Biology, vol. 21, no.
23, pp. 2029–2032.
[60] E. van der Helm, J. Yao, S. Dutt, V. Rao, J. M. Saletin, and
M. P. Walker, “REM sleep depotentiates amygdala activity to
previous emotional experiences,” Current Biology, vol. 21, no.
23, pp. 2029–2032, 2011.
[61] M. Imbesi, S. Yildiz, A. Dirim Arslan, R. Sharma, H. Manev,
and T. Uz, “Dopamine receptor-mediated regulation of neu-
ronal “clock” gene expression,” Neuroscience, vol. 158, no. 2,
pp. 537–544, 2009.
[62] G. Hampp, J. A. Ripperger, T. Houben et al., “Regulation of
monoamine oxidase A by circadian-clock components implies
clock influence on mood,” Current Biology, vol. 18, no. 9, pp.
678–683, 2008.
[63] S. Hood, P. Cassidy, M. P. Cossette et al., “Endogenous
dopamine regulates the rhythm of expression of the clock
protein PER2 in the rat dorsal striatum via daily activation of
D2 dopamine receptors,” Journal of Neuroscience, vol. 30, no.
42, pp. 14046–14058, 2010.
[64] K. Sakamoto, C. Liu, M. Kasamatsu, N. V. Pozdeyev, P.
M. Iuvone, and G. Tosini, “Dopamine regulates melanopsin
mRNA expression in intrinsically photosensitive retinal gan-
glion cells,” European Journal of Neuroscience, vol. 22, no. 12,
pp. 3129–3136, 2005.
[65] P. L. Turner and M. A. Mainster, “Circadian photoreception:
ageing and the eye’s important role in systemic health,” British
Journal of Ophthalmology, vol. 92, no. 11, pp. 1439–1444, 2008.
[66] A. Hartmann, J. D. Veldhuis, M. Deuschle, H. Standhardt,
and I. Heuser, “Twenty-four hour cortisol release profiles in
patients with Alzheimer’s and Parkinson’s disease compared
to normal controls: ultradian secretory pulsatility and diurnal
variation,” Neurobiology of Aging, vol. 18, no. 3, pp. 285–289,
1997.
[67] D. Devos, M. Kroumova, R. Bordet et al., “Heart rate
variability and Parkinson’s disease severity,” Journal of Neural
Transmission, vol. 110, no. 9, pp. 997–1011, 2003.
[68] C. H. Adler and M. J. Thorpy, “Sleep issues in Parkinson’s
disease,” Neurology, vol. 64, supplement 3, no. 12, pp. S12–S20,
2005.
[69] B. Bruguerolle and N. Simon, “Biologic rhythms and Parkin-
son’s disease: a chronopharmacologic approach to considering
fluctuations in function,” Clinical Neuropharmacology, vol. 25,
no. 4, pp. 194–201, 2002.
[70] E. Fertl, E. Auff, A. Doppelbauer, and F. Waldhauser, “Circa-
dian secretion pattern of melatonin in de novo Parkinsonian
patients: evidence for phase-shifting properties of l-dopa,”
Journal of Neural Transmission, vol. 5, no. 3, pp. 227–234, 1993.
[71] E. Fertl, E. Auff, A. Doppelbauer, and F. Waldhauser, “Circa-
dian secretion pattern of melatonin in Parkinson’s disease,”
Journal of Neural Transmission, vol. 3, no. 1, pp. 41–47, 1991.
[72] A. O. Kogan and P. M. Guilford, “Side effects of short-term
10,000-lux light therapy,” American Journal of Psychiatry, vol.
155, no. 2, pp. 293–294, 1998.
Parkinson’s Disease 9

[73] A. R. Artemenko and I. Levin Ia, “The phototherapy of

parkinsonism patients,” Zhurnal Nevrologii i Psikhiatrii imeni
S.S. Korsakova, vol. 96, no. 3, pp. 63–66, 1996.
[74] C. Sobin and H. A. Sackeim, “Psychomotor symptoms of
depression,” American Journal of Psychiatry, vol. 154, no. 1, pp.
4–17, 1997.
[75] C. M. Morin, P. J. Hauri, C. A. Espie, A. J. Spielman, D. J.
Buysse, and R. R. Bootzin, “Nonpharmacologic treatment of
chronic insomnia. An American Academy of Sleep Medicine
review,” Sleep, vol. 22, no. 8, pp. 1134–1156, 1999.
[76] C. M. Morin, R. R. Bootzin, D. J. Buysse, J. D. Edinger, C.
A. Espie, and K. L. Lichstein, “Psychological and behavioral
treatment of insomnia: update of the recent evidence (1998–
2004),” Sleep, vol. 29, no. 11, pp. 1398–1414, 2006.
[77] M. Terman, J. S. Terman, and D. C. Ross, “A controlled trial of
timed bright light and negative air ionization for treatment of
winter depression,” Archives of General Psychiatry, vol. 55, no.
10, pp. 875–882, 1998.
[78] A. Wirz-Justice, F. Benedetti, M. Terman et al., “Chronother-
apeutics (light and wake therapy) in affective disorders,”
Psychological Medicine, vol. 35, no. 7, pp. 939–944, 2005.
[79] J. S. Terman, M. Terman, D. Schlager et al., “Efficacy of brief,
intense light exposure for treatment of winter depression,”
Psychopharmacology Bulletin, vol. 26, no. 1, pp. 3–11, 1990.
[80] M. Terman and J. S. Terman, “Light therapy,” in Principles
and Practice of Sleep Medicine, Elsevier, Philadelphia, Pa, USA,
2005.
[81] M. Terman, C. E. Remé, B. Rafferty, P. F. Gallin, and J. S.
Terman, “Bright light therapy for winter depression: potential
ocular effects and theoretical implications,” Photochemistry
and Photobiology, vol. 51, no. 6, pp. 781–792, 1990.
[82] A. Wirz-Justice, F. Benedetti, and M. Terman, “Inpatient
procedures,” in Chronotherapeutics for Affective Disorders,
Karger, Basel, Switzerland, 2009.
[83] J. A. Horne and O. Ostberg, “A self assessment questionnaire
to determine morningness eveningness in human circadian
rhythms,” International Journal of Chronobiology, vol. 4, no. 2,
pp. 97–110, 1976.
[84] P. F. Gallin, M. Terman, C. E. Reme, B. Rafferty, J. S. Terman,
and R. M. Burde, “Ophthalmologic examination of patients
with seasonal affective disorder, before and after bright light
therapy,” American Journal of Ophthalmology, vol. 119, no. 2,
pp. 202–210, 1995.
[85] J. Schwitzer, C. Neudorfer, H. G. Blecha, and W. W. Fleis-
chhacker, “Mania as a side effect of phototherapy,” Biological
Psychiatry, vol. 28, no. 6, pp. 532–534, 1990.
[86] D. F. Kripke, “Timing of phototherapy and occurrence of
mania,” Biological Psychiatry, vol. 29, no. 11, pp. 1156–1157,
1991.

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